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Jul 2011 Vol 4 No.3
124
North American Journal of Medicine and Science
Review
Do Apparent Overlaps between Schizophrenia and
Autistic Spectrum Disorders Reflect Superficial
Similarities or Etiological Commonalities?
William S. Stone, PhD, Lisa Iguchi, PhD
ABSTRACT
Study Background: Schizophrenia and autism are both
neurodevelopmental disorders that were once considered
to be the same disorder expressed in different
developmental periods. Although they were separated
diagnostically about 40 years ago, they share several
clinical and possibly, etiological features. This paper
reviews overlaps in four domains of function to consider
the issue of whether these similarities are sporadic and
likely to represent superficial similarities, or whether the
disorders are more likely to share some features in
common.
Methods: Representative areas of function were reviewed
and compared for aspects of cognition (nonverbal
reasoning, memory and language), social function
(orienting / joint attention, eye contact and theory of
mind), brain function (structural differences) and
genetics. To facilitate comparisons with schizophrenia, a
focus on high functioning autism / Asperger’s disorder
was utilized, particularly in the sections on cognition and
social function.
Results: Significant similarities (and
characterized comparisons in each domain.
differences)
Conclusions: Disturbed function in similar clinical (in
cognition and social function), neurobiological (brain
volumes) and genetic (e.g., involvement of the same genes
or chromosomal locations) domains in autism and
schizophrenia supports the hypothesis that while they are
distinct disorders, they are not entirely unique.
Additional studies of similarities and differences between
them may thus shed light on common etiological
mechanisms and hopefully, facilitate the development of
novel treatment targets.
[N A J Med Sci. 2011;4(3):124-133.]
KEY WORDS: Autistic spectrum disorder, cognition, social
cognition, schizophrenia spectrum disorder
Autism and schizophrenia are among many psychiatric and
neurological disorders that share overlapping clinical features
and involve widespread psychiatric and cognitive
impairments. Other examples include different dementing
disorders, which often produce similar clinical symptoms in
their later stages, and disorders involving psychosis, such as
schizophrenia and bipolar I disorder with psychotic features.
The situation is complicated somewhat by a reliance on
clinical symptoms to make diagnoses in psychiatry,1 but are
complicated even more so by the nature of the disorders
themselves. Many psychiatric (and other medical) disorders
and normal functions have multiple causes, and many causal
factors may be sufficient, often in combination with other
causal factors, to contribute to the development or
maintenance of a disorder.2,3
(Corresponding Author)
William S. Stone, PhD
Department of Psychiatry
Beth Israel Deaconess Medical Center
Harvard Medical School, Boston, MA, USA
Current postal address:
Harvard Medical School, Department of Psychiatry/BIDMC
401 Park Drive, 2nd Floor East, Boston, MA 02215
Tel: 617-998-5035 Fax: 617-998-5007
Email: [email protected]
The multi-factorial and complex nature of autism and
schizophrenia adds to the difficulty of establishing their
etiologies. Nevertheless, the importance of identifying
etiological factors is often an essential step in the
development of new treatment strategies. While there are
several potential paradigms that might be utilized to progress
towards this goal, one is to assess the potential importance of
overlapping symptoms in these syndromes. This approach
can help determine whether observed similarities reflect
common etiological factors, such as a continuum between
schizophrenic and autistic spectrums, or whether they more
likely reflect superficial similarities, (such as problems in
attention that may result from any number of disparate
causes).
Lisa Iguchi, PhD
Tel: 617-998-5035 Fax: 617-998-5007
Email: [email protected]
In this paper, we focus on apparent overlaps between
schizophrenia and autism spectrum disorders, which both
reflect common, clinically significant spectrums. Until these
Received 7/5/2011; Revised 7/25/2011; Accepted 7/25/2011
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Jul 2011 Vol 4 No.3
disorders came to be viewed as distinct in the 1970s, they
were viewed as different phases of the same problem, with
autism manifesting as an earlier phase of schizophrenia.4,5
Although they are viewed separately now, they do intersect
along several dimensions, including, for example, problems
with social interaction and emotion, verbal and nonverbal
communication, and odd or inflexible behavior. It is not
clear, however, whether these and other shared clinical
features reflect common underlying etiological factors.
Moreover, the question is complicated by heterogeneity of
symptoms, differences in age of onset, environmental factors
and responses to treatment. In the interests of maximizing
clarity and also emphasizing cognition, we will focus
somewhat on adolescents and adults whose overall cognitive
abilities are above IQs of 70 (i.e., above DSM-IV ranges
required for diagnoses of mental retardation).
For the autism spectrum disorders, this mainly includes a
composite group of individuals who are commonly diagnosed
with high-functioning autism/Asperger syndrome (HFA/AS).
Reviews of the schizophrenia spectrum will focus on
schizophrenia itself, but will also include other DSM-IV
disorders such as schizoaffective disorder (depressed type)
and schizotypal personality disorder, where appropriate. The
aim of this paper is not to argue for or against existing
theories in either schizophrenia or autism, but to explore
representative evidence about the nature of overlaps between
them. Evidence for common etiological components, if
present, may then provide an impetus for the development of
research strategies aimed at clarifying etiology further and at
developing/validating clinical interventions.
The remainder of the paper is organized into five sections.
Representative overlaps between schizophrenia and HFA/AS
will be reviewed briefly in four dimensions, including: 1/
cognition, 2/ social functioning, 3/ structural brain
abnormalities, and 4/ genetics. We conclude by considering
implications for etiology, clinical interventions and future
research.
WHAT EVIDENCE IS THERE FOR OVERLAP?
Cognition
Cognitive processes are essential for individuals to interact
with the world and other people in a meaningful way.
Overall, cognitive deficits are generally milder in high
functioning autism (i.e., HFA/AS) than they are in
schizophrenia,6 and more related to social function.7,8 They
are, however, significant clinically, and form the basis of
some cognitive theories of autism.9 Representative examples
of cognitive deficits will be considered for schizophrenia and
HFA/AS in three domains, including (1) nonverbal
reasoning, (2) memory, and (3) language. These cognitive
abilities are all important for social interaction,
communication, and adaptive behavior, and are impaired in
both spectra in various dimensions and to varying degrees.
Nonverbal reasoning
Nonverbal reasoning is instrumental for abstracting the
essence of situations, and for assigning meaning to them. It is
often measured by neuropsychological tasks that involve
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perceiving, organizing, integrating, and associating
information in the service of goal-directed behavior. In most
people, this chain of events happens more or less
automatically. In people with HFA/AS, this chain of events
may happen more deliberately, abnormally, or not at all. This
observation contributes to cognitive theories of autism that
focus on tendencies towards local rather than global
processing of information.10 Similarly, organizing and
integrating information is often impaired in schizophrenia, as
demonstrated, for example, by difficulties in emotion
perception in schizophrenia spectrum illness.11,12 Individuals
with schizophrenia report normal emotional experiences in
the presence of emotionally evocative stimuli, but are often
less expressive and less likely to maintain those emotional
reactions in the absence of the stimuli.13 As with
schizophrenia, emotion perception is impaired in HFA/AS in
some ways,14 but not others. Quintin et al showed recently,
for example, that HFA/AS subjects perceived emotions in
music normally when verbal IQ was controlled.15 Wallace et
al demonstrated impaired facial emotion perception in
HFA/AS individuals who were matched to healthy controls
on age, gender and IQ, but these differences were minimized
for most emotions when facial expressions increased in
intensity.16
Salience is another mediating factor in nonverbal reasoning.
There is an intrinsic and bi-directional relationship between
what we attend to and what is judged to be relevant.
Individuals with schizophrenia often base their actions on
misinformation due to idiosyncratic meaning attached to a
particular stimulus, as reflected in loose associations, over- or
under-inclusive thinking and paranoia.17,18 Individuals with
HFA/AS show particular deficits in salience to social stimuli,
particularly in situations that involve distracters or the need
to switch attention rapidly between different sensory
modalities, objects or locations.19,21 Both groups often fail to
suppress information that is important, but not salient.
Memory
Deficits in declarative memory performance are wellestablished in patients with schizophrenia, but involve
problems with encoding (i.e., learning) more than they
involve problems with memory storage.6,22,23 These deficits
are not only related to other cognitive abnormalities (e.g.,
executive function and attention), but are linked to
hippocampal abnormalities and to clinical symptoms that
cause functional impairment. There are fewer published
studies on declarative memory in HFA/AS than there is in
schizophrenia spectrum disorders, but some conclusions may
be drawn. Individuals with HFA/AS often show normal free
recall, cued recall and recognition,24 particularly for itemspecific material that is subject to rote memorization.
Individuals with HFA/AS show poorer recall, however, as
interference increases, contextual relatedness increases, and
particularly when social contextual information increases.24-28
Similarly, adults with HFA/AS have poorer autobiographical
memories,29,30 which partly reflects difficulties in taking firstperson perspectives.28 Notably, learning/encoding problems
in autism and in schizophrenia are both more prominent than
are problems in recognition, which emphasizes their
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vulnerability to problems in executive function (e.g. in
learning, retrieval, organization and resistance to distraction)
and attention. Thus, despite differences (e.g., memory
performance impairments in schizophrenia are broader and
more robust than they are in HFA/AS), they show significant
similarities as well.
These similarities may be particularly significant with respect
to relational and contextual memory, which involves the
ability to associate and remember names with faces, the
locations of objects or people, and the order in which events
occur. Some researchers attribute declarative memory deficits
in HFA/AS to problems with processing relational and
contextual information.31 Similar deficits have been observed
in individuals with schizophrenia, using associative inference
and transitive inference paradigms.32,33 Almost 20 years ago,
DeLong34 postulated that autism was a developmental
syndrome of hippocampal dysfunction, based on evidence
that the hippocampus is involved in constructing meaning
and integrating new experiences with old ones. Recent
research indicates that the connection between relational and
contextual memory deficits and hippocampal dysfunction in
HFA/AS has to do with preferential use of item-specific
information, rather than with associative learning.25
Procedural memory deficits in individuals with HFA/AS are
sometimes
captured
diagnostically
as
DSM-IV
developmental coordination disorder or as a nonverbal
learning disorder (which is often diagnosed under DSM-IV
cognitive disorder, not otherwise specified), with evidence of
poorer memories for self-performed actions than controls.35
These examples of impaired autonoetic awareness (i.e.,
remembering what is involved in episodic memory
experiences) seem closely related to hippocampal-dependent
relational and contextual memory impairment.
Semantic memory deficits observed in schizophrenia and
HFA/AS are variable. One meta-analysis of 91 studies found
an uneven profile of impairment in individuals with
schizophrenia on semantic tasks involving naming, wordpicture matching, verbal fluency, priming, and categorization
36
. There was a large effect size for naming and verbal
fluency, medium effect size for word-picture matching and
association and small effect sizes for priming and
categorization. The conclusion was that there was a link
between thought disorder and semantic memory impairments
on tests of naming and verbal fluency, though on other tests
the evidence was equivocal. These findings are consistent
with observations of wide semantic boundaries and
generation of atypical exemplars in schizophrenia.37 By
contrast, a PubMed search using key words “semantic
memory autism asperger” resulted in only 7 articles
published between 1998 and 2009. The articles examined
recognition memory, self-other memory, semantic
association, dream content analysis, and using context and
pragmatic language. Thus, the variability in semantic
memory deficits seen in schizophrenia and HFA/AS relates
not only to thought disorder, but also to language, which will
be explored next.
North American Journal of Medicine and Science
Language
Language abnormalities play a prominent role in
schizophrenia and HFA/AS. People with schizophrenia and
HFA/AS have trouble with coherent communication—that is,
with packaging and conveying information in a meaningful
way. But there are subtle differences in how this incoherence
manifests itself. In schizophrenia, it may take the form of
neologisms or loose associations that are characteristic of
thought disorder. Communication difficulties that result from
thought disorder in schizophrenia are at least partially
attributable to neuropsychological deficits (e.g., in
attention/working
memory,
immediate
memory,
organizational sequencing and conceptual sequencing).38
Subjects with HFA/AS often show problems with language,39
which may include awkward timing, phrasing or transitions
during conversations and problems with pragmatic and
prosodic skills, among other abnormalities, though these
individuals (i.e., with IQs in the average range) also tend to
show generally intact formal language capacity.40 One recent
study compared subjects who were 11-20 years old who met
criteria for a clinical high risk (for psychosis) group (CHR), a
first episode psychosis group (FEP), an autistic spectrum
disorders (ASD) group and a typically developing individuals
group (TYP).41 Each of the three clinical groups showed
deficits in social function and atypical development of
language. Notably, the ASD (i.e., HFA/AS subjects) subjects
showed greater grammatical and pragmatic language
symptoms (e.g., delayed echolalia, pedantic speech, and
problems understanding humor, irony and sarcasm) than the
other groups.
One way to assess language functioning is to administer tests
of reading comprehension or narrative writing. Individuals
with schizophrenia are able to read single words (decoding)
but take longer to complete reading comprehension tests and
obtain lower scores.42-44 With schizophrenia, poor
comprehension or writing relates to fundamental problems
with attention and working memory, processing speed, and
extracting and organizing salient information. With HFA/AS,
poor comprehension or writing often occurs as a result of
failure to integrate or assemble complex information to
derive or produce a meaningful whole.
Another way to measure a person‟s ability to access and use
language to demonstrate knowledge is to administer a verbal
fluency test. Both semantic and phonemic fluency are
impaired in schizophrenia and HFA/AS, and may be
associated particularly with deficits in semantic processing.
For example, one study found that deficits in semantic
fluency but not phonologic fluency differentiated a group of
66 young patients at high risk for psychosis from 67 other
psychiatric, help-seeking controls.45 Another study reported a
unique connection between action (verb) fluency and odd
speech in schizophrenia, rather than a general impairment in
language or executive demands that are common to fluency
tasks.46 Citing research that verbs influence causal
attributions that are central to interpersonal communication,
they also linked action-word fluency deficits to deficits in
social interaction.
North American Journal of Medicine and Science
Jul 2011 Vol 4 No.3
In summary, many individuals with either HFA/AS or
schizophrenia show communication difficulties. Some of
these problems are related to thought disorder in both spectra,
but differ somewhat between disorders, with HFA/AS
showing a somewhat broader and extensive set of
communication difficulties, on average.
Social Functioning
Deficits in social function are among the defining features of
autism,39,47 and are among the core features of
schizophrenia.48,49 At least one recent study that compared
subjects with HFA/AS with subjects with schizophrenia on a
range of social cognition measures showed that they
performed similar to each other, but worse than controls on
most measures 50 (but see also 51). As reviewed above, both
groups are affected adversely by cognitive deficits. This
section reviews overlap in several key areas related to social
function, including orienting/joint attention, gaze and eye
contact, and theory of mind.
Orienting, Joint Attention and Visual Processing Style
Joint attention is a kind of social orienting that occurs when
one person turns to look in the same direction that they see
another person looking. It usually emerges reliably between
the ages of 1-2,52,53 and it is one of the foundations of social
interaction because shared attention is directed to objects of
mutual interest. As such, it assumes knowledge of others‟
interests and helps to develop both „theory of mind‟
(described below) and language. Abilities to identify
emotions or other aspects of mental state emerge between the
ages of 3-4.53 Joint attention involves at least two wellresearched phenomena: 1/ facial and emotion recognition,
and 2/ visual processing style. Both of these phenomena
influence social functioning by driving salient aspects of
(particularly novel) social situations.
Individuals with
HFA/AS do not attend well to social aspects of the
environment (though they may attend as well as controls to
non-social stimuli 19), follow other people‟s gaze
spontaneously or make normal eye contact.53 In experimental
settings using cueing tasks and eye movement (saccade)
recordings, however, they can show normal overt orienting
responses in response to explicit eye gaze cues and to arrow
cues.54 One implication of these findings is that cueing, as a
form of rule-based or causal relationship, can be employed to
improve social functioning. Under implicit cueing conditions,
individuals with HFA/AS show impaired ability to integrate
emotion (fear) with gaze direction, which is opposite the
effect seen in schizophrenia.
Further, individuals with schizophrenia show impairments in
recognizing facial affect (particularly fear) and in making
social judgments based on facial features,55,56 but intact
ability to experience emotions. In both HFA/AS and
schizophrenia, there is difficulty modifying behavior based
on implicit facial emotional information. In HFA/AS,
miscuing occurs when a facial emotion is not automatically
taken as a cue,57 or when it is taken as cue but is avoided.58
People with schizophrenia show some difficulties that are
similar to those in HFA/AS. In one study, they did not differ
from controls in gaze discrimination performance, but as
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subjects decided when faces (i.e., facial stimuli) were making
eye contact, different brain regions were activated between
groups when the stimuli were rotated from a head-on view.59
Interestingly, results of studies that examined gaze
discrimination in schizophrenia are mixed.60-62 Miscuing in
schizophrenia is also more likely to occur when a facial
emotion / intention is perceived in error. This can occur as a
function of several factors, including levels of positive
psychiatric symptoms. Pinkham et al showed, for example,
that when subjects with schizophrenia were divided into
groups with and without active paranoid ideation at the time
of the test, that the groups did not differ in overall task
accuracy.63 The paranoid subjects, however, showed more
errors than the non-paranoid subjects, in labeling neutral
faces as angry.
Rondan and Deruelle64 examined visual processing style in
adults with HFA/AS and controls. Both HFA/AS participants
and controls showed a preference for matching targets
according to global features on a task involving hierarchical
stimuli (i.e., they matched small squares arranged in the
shape of a circle to little circles arranged in the shape of a
circle, instead of to small squares arranged in a square).
Compared to controls, HFA/AS participants showed a
preference for details over configuration, however, on a task
involving inter-elemental spatial relationships (i.e., they
matched geometric shapes arranged in the shape of a face to
the same constituent shapes arranged in the shape of a face
with different spatial proportions, instead of to different
constituent shapes in the shape of a face with the same spatial
proportions). Whereas HFA/AS involves problems with static
aspects of visual processing (e.g., perceiving details rather
than configurations), schizophrenia also involves problems
with more dynamic aspects of visual processing. For
example, individuals with schizophrenia show eye tracking
dysfunction in a variety of ways, including trouble
maintaining visual pursuit of predictably moving targets.65,66
Despite differences in temporal aspects of visual processing
between HFA/AS and schizophrenia, there are overlapping
deficits in relying on discrete details or moments instead of
relational information or continuity of information to regulate
behavior.
Eye Contact
Eye contact is an important aspect of gaze and social
behavior in many species,53 that is also among the
foundations of communications and social interaction in
humans.53,67,68 Eye contact helps modulate gaze, orientation
and joint attention, and helps to activate and modulate brain
regions involved in social function.67,68 Cues from eye
contact often inform social perception and influence how we
act or modify our actions (i.e., adapt) in given social
situations.
Individuals with HFA/AS show well-documented deficits in
related areas, such as gaze monitoring and joint attention, as
noted above.39 Based on eye-tracking data, individuals with
autism spectrum disorders showed atypical reflexive gaze by
actively avoiding eye contact or failing to orient to the eyes.58
This effect was seen regardless of whether faces had happy,
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fearful, or neutral expressions, and predicted performance on
an emotion recognition task. These findings suggest that
avoiding eye contact may be a cause, as well as a result of
deficits in emotional facial recognition. Moreover, children
with HFA/AS process eye contact more poorly than typically
developing children, when shown pictures of faces.67,69
Typically developing children performed better when the
faces were shown in upright positions than when they were
shown in inverted positions. Children with autistic spectrum
disorders performed best when the faces were presented in
full frontal views, regardless of whether they were presented
in upright or inverted positions. The autistic children did not
perform as well when facial orientations were turned
somewhat, suggesting that compared to typically developing
children, they processed the facial information abnormally,
such as on the basis of bilateral symmetry.
As noted in the previous section, individuals with
schizophrenia also process eye contact information
differently than controls, even when they show similar levels
of discrimination, behaviorally. Implicit processing of social
cues in individuals with schizophrenia was assessed by
asking them to classify words by pressing “left” or “right”
while facial expressions with eye gaze averted to the left or
right flashed in the background.70 Interestingly, participants
were slower to classify words that were incongruent to the
direction of eye gaze than words that were congruent, but this
effect was observed only for expressions of fear. A similar
effect of fear in capturing attention has also been seen among
individuals with schizophrenia.
Theory of Mind (ToM)
ToM is a construct that accounts for others having beliefs,
wants, plans, or intentions that are distinct from ours. It also
includes an understanding of irony, metaphors and faux pas,
as examples of ways of understanding the meaning or intent
of others‟ statements beyond the literal, concrete meaning of
the words. But any construct of „Other‟ presumes first a
concept of „Self‟. Although the concept of ToM is
multidimensional and complex, there is compelling evidence
that aspects of it are impaired in HFA/AS and in
schizophrenia.53,71-73 Taken as a cognitive mechanism, ToM
operates in a relational context, which as we have seen is
often impaired in schizophrenia and HFA/AS.
In individuals with clinically stable, first-episode
schizophrenia, there may be only a moderate influence of
cognitive deficits on ToM, and impaired ToM may exist
independent of clinical state, alexithymia, and capacity for
empathy.74 Further, there is evidence of a negative
correlation between social anxiety and perspective taking, as
well as a positive correlation between empathy and ToM in
patients with first-episode psychosis relative to patients with
chronic schizophrenia.75 Thus, it may be that the effects of
targeting cognitive impairment and ToM for remediation may
not vary as a function of clinical severity, whereas enlisting
empathy to increase ToM may be more effective earlier than
later in the clinical course of schizophrenia.
North American Journal of Medicine and Science
First-order ToM involves having knowledge of another mind
state. Second-order ToM involves appreciating that another
person holds a different belief, and factoring this other belief
(both that there is another belief, as well as what this belief
is) into his or her own sense of reality (meaning-making).
Stratta and colleagues (2010) found that 12-13% of
schizophrenia patients scored correctly on second-order ToM
but not first-order ToM. It is interesting to speculate about
the clinical features of individuals with schizophrenia who
display intact second-order but impaired first-order ToM. For
example, it is possible that this discrepancy contributes to
ontological instability.76
Consistent with the role of the hippocampus in integrating
autonoetic awareness with episodic and procedural memory
(above), autobiographical memory has been linked with ToM
abilities in individuals with HFA/AS.77 Contrary to evidence
of deficits in facial emotion recognition, however, a recent
study found no differences in performance on the Eyes Test
between individuals with HFA, AS, and controls.78 This may
provide clues for targeting and designing approaches for
intervention; for example, matching cognitive abilities (e.g.,
memory) to salient details of social communication (e.g.,
inferring mental states from eyes instead of the whole face).
Although ToM can be can be dissociated partially from
several related functions, such as cognition and clinical
state,74 it is probably a composite construct that involves a
family of abilities that includes joint attention, eye contact,
emotion processing, perceptual recognition abilities,
empathy, cognitive abilities (e.g., memory, executive
functions) and language, among others.79 Moreover, ToM
develops in accordance with a variety of environmental
experiences, such as parenting, education, training and social
interaction. While the focus of this review involves autism
and schizophrenia, deficits in other neurodevelopmental
disorders, such as attention deficit/hyperactivity disorder
(ADHD) and acquired brain disorders (e.g., traumatic brain
injuries), particularly involving the non-dominant
hemisphere, are also associated with impairments in ToM.8082
The multifactorial nature of ToM contributes to variability
in patterns of impairment in different disorders, as shown in a
recent study that compared individuals with childhood
schizophrenia with children who had autism and with
normally developing children.83 Children with schizophrenia
were impaired in „false-belief‟ tasks, but they showed better
understanding of deception than did the children with autism
(and the normally developing children). The children with
autism showed a broader range of ToM impairments
generally than did the children with schizophrenia.
Findings such as these raise the point that the breadth and
severity of ToM deficits in schizophrenia often varies
between studies.71 State dependence is a moderator variable
that might explain some of this variability, as patients with
higher positive symptoms, such as paranoia and delusions,
often show greater ToM deficits than patients with lower
levels of such symptoms.71,84 A recent meta-analysis
confirmed this view, in part by showing that „remitted‟
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patients showed lower levels of ToM deficits than nonremitted patients.85 The effect sizes of ToM deficits remained
large, however, in remitted patients (Cohen‟s d = 0.80, versus
1.21 in non-remitted patients).
Brain
The nature and extent of abnormal brain function in
schizophrenia and HFA/AS are areas of intense interest and
study. Here we emphasize a few representative areas of
overlap in brain volumes that may underlie similarities in
clinical, cognitive or social dysfunctions. Developmental
features of HFA/AS and schizophrenia are especially relevant
at this level, as is the passage of time as an organizing
principle of adaptation.
Numerous structural and functional brain abnormalities occur
in both schizophrenia and autism, although results vary
between and within disorders, at least partly as a function of
methodological differences between studies.59,67,86-91 A metaanalysis of structural MRI studies in autism showed, for
example, increased volumes in total brain, both hemispheres,
the cerebellum and the caudate.87 Toal et al also found
increased volume in the right caudate, and in more restricted
clusters in the brainstem, right middle frontal gyrus,
precentral and postcentral gyri (that extended bilaterally to
the cingulate gyrus, among other areas).88 Cheung et al, using
a modification of Anatomical Likelihood estimation (ALE),
did not show global differences in gray matter between
subjects with autistic spectrum disorders and controls in most
studies,86 but they did show lower gray matter volumes in
several striato-limbic regions that are also lower in
schizophrenia.86,92 These included the right parahippocampal
gyrus, the posterior cingulate, the putamen, the left insula and
the left thalamus. Somewhat in contrast to HFA/AS,
schizophrenia is associated more with lowered volume than
with increased volume, especially in whole brain and in
hippocampus.89,93 Differences in cerebellar86-88 and
amygdala87,90,91 volumes are reported in some studies, but not
others, within schizophrenia and autism spectrum disorders.
These differences are influenced by both methodological and
other variables (e.g., younger ages were associated with
larger amygdala volumes; see 87).
The question of hippocampal volume abnormalities is less
clear in HFA/AS than it is in schizophrenia. Increased
bilateral hippocampal volumes were reported in children with
HFA,94 whereas differences in adults are more
equivocal.87,95,96 By contrast, decreased hippocampal volume
is characteristic of schizophrenia, with no apparent effect of
duration of illness.89,93 Nevertheless, decreased volumes in
the parahippocamal gyri in both disorders implicate both the
hippocampal formation and the medial temporal lobe more
generally in their neuropathologies. It should be emphasized
that the hippocampus is also a part of a broader system
involving the social environment. Structural abnormalities
early in development-such as altered hippocampal volumesshould correspond to abnormal development of other brain
structures and related processes. This is borne out to some
degree by evidence of association cortex and white matter
abnormalities in HFA/AS, and by research that defines
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HFA/AS and schizophrenia as disorders of integration and
connectivity.97,98 In schizophrenia, smaller hippocampal
volumes co-exist with problems discriminating relevant from
irrelevant information or discerning figure and ground
relationships, as demonstrated by research on thalamic lateral
inhibition and sensory gating paradigms, respectively.99,100
One study found decreased gray matter volume in the right
insula in adults with pervasive developmental disorders
versus controls, and that gray matter volume correlated
negatively with Autism Spectrum Quotient scores.101 Other
studies involving HFA/AS relate social and cognitive deficits
to inefficient connectivity in the mirror neuron system and
between limbic and prefrontal areas in HFA/AS.102,103
Genetics
Like many complex psychiatric disorders and normal mental
abilities, schizophrenia and autism result from genetic
etiological components that interact with environmental
factors to facilitate either optimal or disordered function.104
Evidence for a genetic influence in schizophrenia is
compelling at this point,3,105 based on both behavioral genetic
and molecular biologic studies.106-109 One recent review of
twin studies showed, for example, that variance attributable
to heritability was about 84%, and that if one sibling
developed the disorder, the risk to the other sibling would
increase about 12-fold.106 Although linkage studies have had
little success in identifying genes that contribute to the
development of schizophrenia,105 association studies have
identified many genes involved in neuronal signaling or other
aspects of brain structure and function whose dysfunction
might contribute to schizophrenia.109 Several of these genes
may be related to either the diagnostic category of
schizophrenia, or to quantitative endophenotypes for
schizophrenia. A recent study from the Consortium on the
Genetics of Schizophrenia (COGS), for example, examined
12 heritable endophenotypes110 in relation to 1594 single
nucleotide polymorphisms (SNP) identified from 94 genes.111
The 47 strongest SNP-endophenotype combinations
exceeded the number of significant findings expected to
occur by chance alone.
Other paradigms have also shed light on genetic mechanisms
involved in schizophrenia. These include recent work
showing, for example, differences in gene expression
between subjects with schizophrenia, bipolar disorder and
controls,112 gene splicing113 and abnormalities in genomic
copy number variants (CNVs).108
Like schizophrenia, autism (including HFA/AS) has a
significant genetic component. In their review of twin
studies, Glatt et al reported a heritability estimate of 93% for
autism, with a relative risk of 22 for siblings if one twin
develops autism (i.e. they are 22 times more likely to develop
autism than are individuals drawn from the general
population). Similar to the notion of a schizophrenia
spectrum in which non-psychotic relatives show milder
features of schizophrenia,114 non-autistic relatives of
individuals with autism often show milder features of
autism.115 Moreover, numerous candidate genes have been
proposed to contribute to the disorder,116 and many CNVs
have been reported.117
130
Jul 2011 Vol 4 No.3
North American Journal of Medicine and Science
Although family studies of schizophrenia and of autism show
consistently elevated rates of disorders presumed to lie in the
schizophrenia and autistic spectrums respectively, it is
notable that diagnostic overlap also occurs. In one study, for
example, half of a group of individuals with autism (not
restricted to HFA/AS) also met DSM-IV diagnostic criteria
for schizophrenia, disorganized type.118 In another study,
20% of subjects in a clinical high risk group for psychosis
and a first episode psychosis group met diagnostic criteria for
an autistic spectrum disorder.41 A few studies showed that
parental diagnoses of schizophrenia were associated with
elevated rates of autism in offspring.119,120
Forty years after schizophrenia and autism separated
diagnostically into distinct disorders, however, the purpose of
these comparisons is not to conflate them again. Despite
apparent similarities at several levels of analysis, they remain
distinct entities, with important differences in clinical
phenotypes, age of onset, neurobiological mediation and
treatment. Each of the domains reviewed in this paper
showed significant differences in addition to the similarities.
Nevertheless, the similarities in phenotypes (cognition, social
function and brain structure) and genotypes (overlapping
genes and genetic mechanisms) support hypotheses that these
disorders are not entirely unique, either.86,108,117
Moreover, certain co-morbid medical conditions are elevated
in both disorders, such as amyotrophic lateral sclerosis (ALS)
and several bleeding disorders (e.g., Gaucher‟s disease), and
may be related to similar chromosomal regions.121
Interestingly, overlapping genetic mechanisms do not
necessarily produce the same phenotypic effects. Crespi and
Thiselton showed evidence, for example, that alleles at
DRB1 influence risk for rheumatoid arthritis, schizophrenia
and autism in a pleiotropic manner.122 Alleles at DRB1*04
increased risk for arthritis and autism but decreased it for
schizophrenia, while alleles at DRB1*13 alleles reduce the
risk for arthritis and autism, but increase it for schizophrenia.
Deletions in the 22q11.2 region (also known as
velocardiofacial syndrome) is a well-known example of a
CNV that confers risk for both autism and for
schizophrenia.117 Copy number variants at other
chromosomal locations, such as 16p11.2, are also associated
with schizophrenia, autism and other disorders.123-125
Similarly, CNVs that were associated with another
neurodevelopmental disorder, ADHD, were reported in both
autism and schizophrenia at the same chromosomal loci.126 In
addition to chromosomal locations, several candidate genes
have been implicated in both disorders, such as disrupted in
schizophrenia (DISC1),127,128 contactin-associated protein-2
(CNTNAP2)117 and others.129
Moreover, the overlap between schizophrenia and autism
may be part of a broader set of overlaps between these
neurodevelopmental disorders and others, such as ADHD,
bipolar disorder and intellectual disability.108,126 In this view,
common pleiotropic risk alleles and rarer risk alleles,
together with protective genetic factors and other
environmental and biological factors can produce a number
of different, heterogeneous disorders that may share certain
features in common, but differ along other dimensions.
SUMMARY
This review focused on several substantive areas of overlap
between schizophrenia and autism, with an emphasis on
HFA/AS. Representative examples involving cognitive
deficits, social dysfunction, brain abnormalities and genetics
show significant areas of correspondence between these two
conditions, and the spectra they represent. It should be noted
that while the sections on cognition and social function
focused on HFA/AS, the sections on brain function and
genetics did not maintain that distinction to the same degree,
but showed similar levels of correspondence with
schizophrenia. Moreover, the areas selected for review,
though important functionally or etiologically, are only a
subset of domains in which the two conditions might overlap.
Other proposed areas of overlap are related to clinical
symptoms (including paranoia and psychosis), abnormal
information processing (as shown by „sensory gating‟
problems), minor physical anomalies (such as neurological
„soft signs) and vitamin D deficiency during pregnancy, for
example.86
Both the etiological and the functional significance of these
areas of overlap are uncertain at this time. If several major
dimensions of function share pathological and possibly
etiological similarities, however, then the study of these
concordances may shed additional light on the nature of both
disorders. Among the questions future research may help to
resolve are which problems are more etiological, and which
are more resultant. We proposed that psychosis, for example,
despite its disruptive effects in schizophrenia, was more
likely a non-specific consequence of earlier, etiological
factors.130
The resolution of such issues, in turn, may facilitate the
development of novel treatment targets, or suggest
approaches that are known to be useful for one disorder, for
use with the other disorder. Antipsychotic medications, for
example, which have long been first-line treatments for
schizophrenia, have been utilized more recently in other
psychiatric
conditions,
including
autism.131
The
administration of oxytocin to subjects with either
schizophrenia or with autism, shows preliminary promise of
improving social cognition, mood problems and psychotic
symptoms in both autism and schizophrenia.132-134 In this
instance, positive effects in any of these clinically significant
domains in either the schizophrenia or autism spectra is likely
to encourage investigation of these problems in the other
spectra. Similarly, non-pharmacological treatments such as
cognitive enhancement therapy, which is a promising
intervention for cognitive problems in schizophrenia,135,136
may have applications for autism as well. More generally, the
growing range of apparent similarities between autism and
schizophrenia raises the potentially significant possibility that
etiological overlaps of their spectra may extend to productive
overlaps in therapeutic intervention strategies.
North American Journal of Medicine and Science
Jul 2011 Vol 4 No.3
ACKNOWLEDGEMENTS
This work was supported in part by Ortho-McNeil Janssen
Scientific Affairs, LLC, and by National Institute of Mental
Health Grant RO1-MH065562 (COGS; Consortium on the
Genetics of Schizophrenia).
22.
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